*Laboratory of Experimental Thrombosis and Laboratory of the Inflammatory Process, Institute of Experimental Medicine-CONICET, National Academy of Medicine. Buenos Aires, Argentina; Biotechnology and Molecular Biology Institute, CONICET-UNLP, La Plata, Argentina.
*Laboratory of Experimental Thrombosis and Laboratory of the Inflammatory Process, Institute of Experimental Medicine-CONICET, National Academy of Medicine. Buenos Aires, Argentina; Biotechnology and Molecular Biology Institute, CONICET-UNLP, La Plata, Argentina
J Leukoc Biol. 2016 Jan;99(1):153-62. doi: 10.1189/jlb.3A0415-161R. Epub 2015 Aug 28.
In addition to being key elements in hemostasis and thrombosis, platelets amplify neutrophil function. We aimed to gain further insight into the stimuli, mediators, molecular pathways, and regulation of neutrophil extracellular trap formation mediated by human platelets. Platelets stimulated by lipopolysaccharide, a wall component of gram-negative bacteria, Pam3-cysteine-serine-lysine 4, a mimetic of lipopeptide from gram-positive bacteria, Escherichia coli, Staphylococcus aureus, or physiologic platelet agonists promoting neutrophil extracellular trap formation and myeloperoxidase-associated DNA activity under static and flow conditions. Although P-selectin or glycoprotein IIb/IIIa were not involved, platelet glycoprotein Ib, neutrophil cluster of differentiation 18, and the release of von Willebrand factor and platelet factor 4 seemed to be critical for the formation of neutrophil extracellular traps. The secretion of these molecules depended on thromboxane A(2) production triggered by lipopolysaccharide or Pam3-cysteine-serine-lysine 4 but not on high concentrations of thrombin. Accordingly, aspirin selectively inhibited platelet-mediated neutrophil extracellular trap generation. Signaling through extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, and Src kinases, but not p38 or reduced nicotinamide adenine dinucleotide phosphate oxidase, was involved in platelet-triggered neutrophil extracellular trap release. Platelet-mediated neutrophil extracellular trap formation was inhibited by prostacyclin. Our results support a role for stimulated platelets in promoting neutrophil extracellular trap formation, reveal that an endothelium-derived molecule contributes to limiting neutrophil extracellular trap formation, and highlight platelet inhibition as a potential target for controlling neutrophil extracellular trap cell death.
除了在止血和血栓形成中起关键作用外，血小板还能放大中性粒细胞的功能。我们旨在进一步深入了解由人血小板介导的中性粒细胞细胞外陷阱形成的刺激物、介质、分子途径和调节。血小板被脂多糖（革兰氏阴性菌细胞壁的组成部分）、Pam3-半胱氨酸-丝氨酸-赖氨酸 4（革兰氏阳性菌脂肽的模拟物）、大肠杆菌、金黄色葡萄球菌或促进中性粒细胞细胞外陷阱形成和髓过氧化物酶相关 DNA 活性的生理性血小板激动剂刺激。虽然 P-选择素或糖蛋白 IIb/IIIa 不参与其中，但血小板糖蛋白 Ib、中性粒细胞分化抗原 18，以及血管性血友病因子和血小板因子 4 的释放似乎对中性粒细胞细胞外陷阱的形成至关重要。这些分子的分泌依赖于由脂多糖或 Pam3-半胱氨酸-丝氨酸-赖氨酸 4 触发的血栓烷 A2 产生，但不依赖于高浓度的凝血酶。因此，阿司匹林选择性抑制血小板介导的中性粒细胞细胞外陷阱生成。细胞外信号调节激酶、磷脂酰肌醇 3-激酶和Src 激酶的信号转导，而不是 p38 或还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶，参与了血小板触发的中性粒细胞细胞外陷阱释放。前列腺素 I2 抑制血小板介导的中性粒细胞细胞外陷阱形成。我们的结果支持受刺激的血小板在促进中性粒细胞细胞外陷阱形成中的作用，揭示了一种内皮细胞衍生的分子有助于限制中性粒细胞细胞外陷阱形成，并强调了血小板抑制作为控制中性粒细胞细胞外陷阱细胞死亡的潜在靶点。
